Summary The majority of the human transcriptome consists of long non-coding RNAs (lncRNAs), which regulate the expression and function of protein-coding genes, immune cell development, differentiation, and response to infections. The role of lncRNAs in HIV-infected cells and how the host lncRNAs impact the replication and persistence of HIV infection is not known. The objective of this proposal is to identify host lncRNAs that influence viral replication, cellular and immune responses to infection and molecular mechanisms of their action. Infections induce global changes in lncRNA expression and pathogens are believed to impact immune cell functions through differential induction of regulatory lncRNAs. Our preliminary data showed significant changes in cellular lncRNA expression induced by HIV infection. Several of these lncRNAs showed significant differential expression in CD4+T cells from elite controllers as compared to chronically infected patients or uninfected individuals. We hypothesize that HIV infection hijacks host cellular and immune machinery through differential expression of cellular lncRNAs for facilitating virus replication. We will investigate if the HIV-induced lncRNAs regulate protein- coding genes and modulate the immune response (Aim 1) and dissect the role of HIV-induced lncRNAs in viral replication (Aim 2). We will determine if the significant differential expression of candidate lncRNAs in elite controllers contributes to viral inhibition and immune responses (Aim 3). We will pursue these aims using an innovative combination of molecular and biochemical techniques and cellular models. In addition, we will describe a wide variety of functional information for novel lncRNAs, such as expression, cellular localization and their influence of protein-coding genes. The proposed research is significant because it will determine which host lncRNAs impact HIV replication and could be used as therapeutic targets. It is also significant because it will develop a platform that can be extended to study other types of host non-coding RNAs and open new avenues for host-directed therapy. The expected outcome of this work is an understanding of which lncRNAs contribute to clinical outcomes of HIV infection. The results will have a significant impact because they will establish a better understanding of lncRNAs in HIV infection and immune response and lay the groundwork for development of interventions to treat and eventually eradicate HIV infection.